Abstract
BACKGROUND: Primary membranous nephropathy (PMN) is a leading cause of nephrotic syndrome in adults. In some patients, PMN can be severe or continue to worsen even after 6 months of supportive treatment. Rituximab and cyclophosphamide with steroids are used to treat moderate-risk or high-risk PMN patients, but the comparative efficacy and safety of rituximab and cyclophosphamide with steroids in patients with PMN remains debated. METHODS: We searched PubMed, Embase and the Cochrane Library for the time period through November 2025 to identify randomized controlled trials and cohort studies that evaluated rituximab compared with cyclophosphamide for the treatment of PMN. The primary outcomes were complete remission (CR), partial remission (PR), and total remission (TR = PR+CR). The secondary outcomes included the relapse rate, adverse events (AEs), and serious adverse events (SAEs). The random effects model (DerSimonian-Laird method) was used to estimate relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: Eleven studies (N = 1068) were eligible for final inclusion. Rituximab showed similar efficacy to cyclophosphamide with steroids in inducing complete or partial remission at 6 months (RR, 0.82; 95% CI, 0.60-1.10; p = 0.19; I(2) = 0%) and 12 months (RR, 0.85; 95% CI, 0.66-1.10; p = 0.21; I(2) = 0%). Similarly, rates of CR were comparable between the two treatment groups at 6 months (RR, 0.97; 95% CI, 0.33-2.89; p = 0.95; I(2) = 0%) and 12 months (RR, 0.54; 95% CI, 0.26-1.12; p = 0.10; I(2) = 0%). There were no significant differences in the incidence of AEs or SAEs between RTX and cyclophosphamide with steroids. The RRs were 0.76 (95% CI, 0.46-1.28; p = 0.30; I(2) = 51%) and 1.00 (95% CI, 0.50-2.00; p = 1.00; I(2) = 0%), respectively. CONCLUSIONS: The current limited evidence suggests that RTX treatment has comparable efficacy and safety to cyclophosphamide with steroids in PMN patients at moderate risk or high risk. Further large-scale, longer follow-up, well-designed RCTs on head-to-head comparisons of the safety and efficacy of rituximab versus cyclophosphamide with steroids are urgently needed.